Tumor-Targeting and Microenvironment-Responsive Smart Nanoparticles for Combination Therapy of Antiangiogenesis and Apoptosis
Tumor-Targeting and Microenvironment-Responsive Smart Nanoparticles for Combination Therapy of Antiangiogenesis and Apoptosis
复制标题
用于抗血管生成和细胞凋亡联合治疗的肿瘤靶向和微环境响应型智能纳米颗粒
DOI：
10.1021/nn400548g
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发表时间：
2013-03-01
期刊：
影响因子：
17.1
通讯作者：
Jiang, Chen
中科院分区：
文献类型：
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作者：
Huang, Shixian;Shao, Kun;Jiang, Chen
肿瘤微环境如肿瘤细胞外pH（pHe）和基质金属蛋白酶2（MMP 2）的降低已被广泛研究，这促进了微环境响应型药物传递系统的发展。利用这些独特的功能，我们构建了一种由降低的pHe和MMP 2双重触发的可激活的细胞穿透肽（dtACPP），并成功开发了一种以dtACPP为修饰的智能纳米颗粒系统，可同时双重负载基因药物和化疗药物。全身给药后，dtACPP修饰的纳米颗粒通过增强的渗透性和滞留效应具有被动的肿瘤靶向能力。然后激活dtACPP以暴露细胞穿透肽，从而驱动纳米颗粒内化到肿瘤内细胞中。由于血管生成与肿瘤细胞在肿瘤生长过程中可能相互促进，因此将抗血管生成与凋亡相结合对肿瘤治疗具有重要意义。血管内皮生长因子（VEGF）在血管生成中起重要作用，抗VEGF治疗可明显降低血管密度，延缓肿瘤生长。多柔比星（DOX）化疗能有效杀伤肿瘤细胞。在此，利用dtACPP修饰的纳米颗粒共同递送表达靶向VEGF（shVEGF）和DOX的干扰RNA的质粒（命名为dtACPPD/shVEGF-DOX）导致肿瘤内血管的有效关闭和细胞凋亡。dtACPPD/shVEGF-DOX在有效给药的前提下，表现出良好的肿瘤靶向性，全身给药后副作用小，具有理想的抗肿瘤疗效。
Tumor microenvironment, such as the lowered tumor extracellular pH (pHe) and matrix metalloproteinase 2 (MMP2), has been extensively explored, which promotes the development of the microenvironment-responsive drug delivery system. Utilizing these unique features, an activatable cell-penetrating peptide (designated as dtACPP) that is dual-triggered by the lowered pHe and MMP2 has been constructed, and a smart nanoparticle system decorating with dtACPP has been successfully developed, which could dual-load gene drug and chemotherapeutics simultaneously. After systemic administration, dtACPP-modified nanoparticles possess passive tumor targetability via the enhanced permeability and retention effect. Then dtACPP would be activated to expose cell-penetrating peptide to drive the nanoparticles internalization into the intratumoral cells. As angiogenesis and tumor cells might be mutually improved in tumor growth, so combining antiangiogenesis and apoptosis is meaningful for oncotherapy. Vascular endothelial growth factor (VEGF) is significant in angiogenesis, and anti-VEGF therapy could decrease blood vessel density and delay tumor growth obviously. Chemotherapy using doxorubicin (DOX) could kill off tumor cells efficiently. Here, utilizing dtACPP-modified nanoparticles to co-deliver plasmid expressing interfering RNA targeting VEGF (shVEGF) and DOX (designated as dtACPPD/shVEGF-DOX) results in effective shutdown of blood vessels and cell apoptosis within the tumor. On the premise of effective drug delivery, dtACPPD/shVEGF-DOX has demonstrated good tumor targetability, little side effects after systemic administration, and ideal antitumor efficacy.